Pi3k/Akt Promotes Feedforward Mtorc2 Activation Through Ikk Alpha

The ser-thr Akt plays a critical role in the regulation of cell survival, cell growth and proliferation, as well as energy metabolism and is dysregulated in many cancers. The regulation of Akt activity depends on the phosphorylation at two sites: (i) Thr308 in the activation loop by phosphoinositide-dependent kinase-1 (PDK1) and (ii) Ser473 hydrophobic motif at the carboxyl terminus by a second activity termed PDK2, which is the mTORC2 complex composed of mTOR, rictor, and Sin1. Previously we demonstrated that IKK alpha, a component of the IKK complex that controls NF-kappa B activation, participates in the Akt-dependent regulation of mTORC1. Here we have explored a potential involvement of IKK alpha in controlling Akt activity and whether this may involve mTORC2. The experiments show that IKK alpha associates with mTORC2 in several cancer cells in a manner dependent on PI3K/Akt activity and that IKK alpha positively promotes Akt phosphorylation at Ser473 and at Thr308. Moreover, IKK alpha enhances mTORC2 kinase activity directed to Akt on Ser473 and Akt-mediated phosphorylation of FOXO3a and GSK3 beta, but not other Akt-associated targets such as TSC2 and PRAS40, indicating the existence of multiple mechanisms of Akt activation in cells. In addition, loss of IKK alpha suppresses growth factor-induced Akt activation associated with mTORC1 inhibition. These results indicate that IKK alpha serves as a feedforward regulator of mTORC2 and that IKK alpha could serve as a key therapeutic target to block mTORC2 and Akt activation in some cancers.